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Food intake can alter the pharmacokinetics of certain medications, including changes in their oral bioavailability, which is of particular concern for extended-release (ER) opioids because of the high drug loads. Two randomized, open-label studies assessed the effect of food on the pharmacokinetics of single and multiple doses of hydrocodone ER formulated with CIMA® Abuse-Deterrence Technology. Healthy subjects in fed and fasted states received single 90-mg doses of hydrocodone ER (Studies 1 and 2) or multiple doses of hydrocodone ER (45 mg twice daily on days 2–3, 60 mg twice daily on days 4–5, 90 mg twice daily on days 6–10, and 90 mg once in the morning on day 11) (Study 2). Naltrexone was administered to minimize opioid-related adverse events. Pharmacokinetic parameters included maximum hydrocodone plasma concentration (C max) and area under the concentration-versus-time curve from time 0 to infinity (AUC0–∞) in Study 1 (day 1) and for one dosing interval at steady state (AUCτ,ss) in Study 2 (day 11). Before conducting the multiple-dose study, single-dose data were fitted with a population pharmacokinetic methodology. In total, 40 subjects were randomized to Study 1 and 43 subjects were randomized to Study 2. While overall exposure (AUC0–∞) was relatively similar (least squares mean ratio [90% CI]: 1.11 [1.06–1.16]), results indicated that the single-dose C max was 40% higher under fed versus fasted conditions (least squares mean ratio [90% CI]: 1.40 [1.31–1.51]; Study 1). Modeling of single-dose data predicted that the effect of food would be much less at steady state [predicted fed:fasted C max at steady state (C max,ss) and AUCτ,ss ratios of 1.18 and 1.09, respectively]. The multiple-dose study results validated these predicted ratios and indicated that the steady-state 90% CIs were within 0.80–1.25 for the fed:fasted C max,ss (1.14 [1.07–1.21]) and AUCτ,ss (1.11 [1.04–1.17]) parameters, indicating that clinically meaningful food effects at steady state are not expected. No evidence of an effect of food was found on the pharmacokinetics of hydrocodone ER after multiple days of twice-daily dosing.

Background Greater drug content requirements for extended-release (ER) opioids necessitate greater protection against dose dumping. Hydrocodone ER employs the CIMA® Abuse-Deterrence Technology platform, which provides resistance against rapid release of the active moiety when the tablet is manipulated or taken with alcohol. Objective Assess effects of alcohol on hydrocodone ER pharmacokinetics. Study Design Open-label, crossover (January 25–April 30, 2010). Setting Single center. Participants Forty healthy adults. Intervention Subjects received all four treatments in a randomized manner (separated by a minimum 5-day washout): hydrocodone ER 15 mg with 240 mL water and 240 mL orange juice containing 4, 20, and 40 % alcohol in a fasted state. Naltrexone was administered to minimize opioid-related adverse events. Main Outcome Measure Effect of alcohol on pharmacokinetics of hydrocodone ER assessed by comparing systemic exposure [maximum plasma drug concentration (Cmax) and area under the plasma drug concentration-versus-time curve from time 0 to infinity (AUC0–∞)] after administration with alcohol or with water. Results Geometric means ratios of hydrocodone ER with 4, 20, and 40 % alcohol relative to water were 1.05, 1.09, and 1.14, respectively, for Cmax and 1.07, 1.13, and 1.17, respectively, for AUC0–∞. All 90 % confidence intervals for these geometric means ratios fell within the limits of 0.8 and 1.25. Increasing alcohol concentrations did not notably affect systemic exposure but were associated with increased adverse events. Conclusions Hydrocodone ER tablets were resistant to dose dumping when administered with alcohol in healthy subjects based on similar systemic exposures observed across all treatments.

A hydrocodone extended-release (ER) formulation employing the CIMA® Abuse-Deterrence Technology platform was developed to provide resistance against rapid release of hydrocodone when tablets are comminuted or taken with alcohol. This study evaluated the pharmacokinetics of three hydrocodone ER tablet prototypes with varying levels of polymer coating to identify the prototype expected to have the greatest abuse deterrence potential based on pharmacokinetic characteristics that maintain systemic exposure to hydrocodone comparable to that of a commercially available hydrocodone immediate-release (IR) product. In this four-period crossover study, healthy subjects aged 18–45 years were randomized to receive a single intact, oral 45-mg tablet of one of three hydrocodone ER prototypes (low-, intermediate-, or high-level coating) or an intact, oral tablet of hydrocodone IR/acetaminophen (APAP) 10/325 mg every 6 h until four tablets were administered, with each of the four treatments administered once over the four study periods. Dosing periods were separated by a minimum 5-day washout. Naltrexone 50 mg was administered to block opioid receptors. Blood samples for pharmacokinetic assessments were collected predose and through 72 h postdose. Parameters assessed included maximum observed plasma hydrocodone concentration (C max), time to C max (t max), and area under the concentration-time curve from time 0 to infinity (AUC0–∞). Mean C max values were 49.2, 32.6, and 28.4 ng/mL for the low-, intermediate-, and high-level coating hydrocodone ER tablet prototypes, respectively, and 37.3 ng/mL for the hydrocodone IR/APAP tablet; respective median t max values were 5.9, 8.0, 8.0, and 1.0 h. Total systemic exposure to hydrocodone (AUC0–∞) was comparable between hydrocodone ER tablet prototypes (640, 600, and 578 ng·h/mL, respectively) and hydrocodone IR/APAP (581 ng·h/mL). No serious adverse events or deaths were reported. The most common adverse events included headache (26 %) and nausea (18 %). All three hydrocodone ER tablet prototypes (low-, intermediate-, and high-level polymer coating) demonstrated ER pharmacokinetic characteristics. The hydrocodone ER tablet prototype with the high-level coating was selected for development because of its comparable exposure to the hydrocodone IR/APAP formulation and potentially increased ability to resist rapid drug release upon product tampering because of a higher polymer coating level. All study medications were well tolerated in healthy naltrexone-blocked volunteers.

Background: Fentanyl buccal tablet (FBT) is indicated for the treatment of breakthrough pain in patients who are already receiving, and who are tolerant to, opioid therapy for underlying, persistent cancer pain. Breakthrough pain may be severe or excruciating, and some patients may require high doses of rapid-onset opioids to obtain adequate analgesia. Objective: The objective of this study was to assess the dose proportionality of FBT over a range of 600–1300 μg in healthy subjects. Methods: This was a randomized, open-label, four-period, crossover, single-centre study of FBT (Fentora®) conducted in healthy adult subjects who were not tolerant to opioids. The study included 120 men and women aged 18–45 years with a body mass index of 20–30 kg/m2 who had no clinically significant findings on medical and psychiatric histories, physical examination, ECG or standard clinical laboratory tests, and who had a negative urine screen for drugs and alcohol. Eligible subjects were randomized to one of four dose sequences: ABDC, BCAD, CDBA and DACB, where A, B, C and D were FBT doses from lowest to highest (600, 1000, 1200 and 1300 μg). Each dose of FBT was separated by a minimum of 7 days. Naltrexone 50 mg was administered to block the opioid receptor-mediated effects of fentanyl. Plasma fentanyl concentration was measured through 72 hours after placement of FBT. The main outcome measures, maximum plasma fentanyl concentration (Cmax) and area under the plasma drug concentration versus time curve from time zero to infinity (AUC∞), were analysed to determine dose proportionality. Other pharmacokinetic parameters were also evaluated. Dose proportionality was concluded if the two-sided 90% confidence intervals (CIs) for the slopes of the Cmax versus dose and AUC∞ versus dose curves were completely contained within the range of 0.711–1.289. The safety and tolerability of FBT were assessed throughout the study. Results: The slope for Cmax versus dose was 0.8627 (90% CI 0.7730, 0.9525), and the slope for AUC∞ versus dose was 0.9330 (90% CI 0.8738, 0.9922). Given that the CIs for Cmax and AUC∞ were within the predefined range of 0.711–1.289, dose proportionality was concluded over the 600–1300 μg range. The mean dose-normalized plasma fentanyl concentration reached 80% of Cmax within 25 minutes; plasma fentanyl concentration was maintained at this level for 3 hours after dose. No unexpected safety or tolerability concerns were noted in the naltrexone-blocked healthy subjects. Seventy-four subjects (68%) experienced adverse events (AEs); all were mild (56 [51%]) or moderate (18 [17%]). The most common AEs were nausea, dizziness and headache. No serious AEs were reported. Conclusion: The dose proportionality of FBT from 600–1300 μg was shown in healthy subjects. Based on the data, when FBT is titrated up to 1300 μg, a predictable and linear increase in systemic exposure can be expected. Currently, FBT is approved up to 800 μg. This study provides pharmacokinetic data to support a potential, expanded therapeutic dose range of FBT.

This open-label, crossover study evaluated the dose proportionality of a hydrocodone extended-release (ER) tablet employing the CIMA® Abuse-Deterrence Technology platform. Healthy volunteers were randomized to receive single doses of hydrocodone ER 15, 30, 45, 60, and 90 mg separated by a minimum 14-day washout. Subjects received naltrexone to minimize opioid-related adverse events (AEs). Blood samples were collected for 72 h after each hydrocodone administration. Pharmacokinetic measures included maximum observed plasma hydrocodone concentration (C max) and area under the plasma concentration–time curve from time zero to infinity (AUC∞). Dose proportionality was concluded if the confidence interval (CI) of the slope of the regression line for C max and AUC∞ versus dose fell within 0.875–1.125. In total, 60 subjects were evaluable for pharmacokinetics. The mean C max was 12.6, 20.7, 30.3, 41.2, and 62.5 ng/mL and the mean AUC∞ was 199, 382, 592, 766, and 1189 ng·h/mL for hydrocodone ER 15, 30, 45, 60, and 90 mg, respectively. C max and AUC∞ increased linearly with increasing dose. The 90 % CIs of the slope of the regression line for C max (0.880–0.922) and AUC∞ (0.984–1.026) indicated systemic exposure to hydrocodone increased in a dose-proportional manner. In these naltrexone-blocked subjects, no increased incidence of AEs was apparent with increasing dose. Hydrocodone exposure increased in a dose-proportional manner after administration of hydrocodone ER 15–90 mg tablets in healthy, naltrexone-blocked subjects.

The fentanyl buccal tablet (FBT) is formulated to enhance the rate and extent of fentanyl absorption across the buccal mucosa. FBT is indicated for the management of breakthrough pain (a transient flare of pain on a background of chronic pain otherwise controlled by treatment with opioids) in patients with cancer who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain. This study assessed the bioequivalence of a single 400-microg dose of FBT following buccal (i.e. above a molar tooth between the upper gum and cheek) and sublingual (i.e. placed under the tongue) placement in order to provide an alternative option to patients.Healthy subjects were randomized to receive one FBT 400 microg buccally and sublingually (with naltrexone to minimize opioid effects) in an open-label, crossover design. Bioequivalence, as determined from the maximum plasma drug concentration (C(max)) and the area under the plasma drug concentration-time curve from time 0 to infinity (AUC(infinity)), was established if the 90% confidence interval (CI) for the ratio of the means of sublingual/buccal values fell within the range of 0.80 to 1.25.Ninety subjects were enrolled (67 men, 23 women; median age 24 years), and 78 completed the study. The criteria for bioequivalence were met for both C(max) and AUC(infinity) for the two sites of tablet placement: sublingual/buccal ratio for C(max) = 0.868 (90% CI 0.815, 0.924); sublingual/buccal ratio for AUC(infinity) = 0.947 (90% CI 0.901, 0.995). Buccal and sublingual placement resulted in similar values for both AUC from time 0 to t(max') (AUC(tmax')), where t(max') is the median time to C(max) of a single 400-microg dose of FBT administered buccally (mean [SD]: 0.35 [0.16] ng . h/mL buccal; 0.35 [0.16] ng . h/mL sublingual) and for time to C(max) (median [range]: 0.75 [0.33-3.13] hours buccal; 0.78 [0.17-3.00] hours sublingual). FBT was generally well tolerated following placement at both sites in healthy volunteers administered naltrexone.The results of this study support sublingual FBT placement as a viable alternative to buccal placement in patients who may require an alternate administration site.

Patients with cancer, particularly those undergoing chemotherapy or radiotherapy, may develop oral mucositis. This is the first study to investigate the absorption profile of fentanyl buccal tablet (FBT) - an effervescent formulation of fentanyl indicated for the management of breakthrough pain in opioid-tolerant cancer patients - in patients with or without oral mucositis.In this open-label study, patients with or without oral mucositis self-administered a single 200 microg dose of FBT by placing the tablet between the upper gum and cheek above a molar tooth. Venous blood samples for measurement of plasma fentanyl concentrations were collected at regular intervals up to 8 hours following FBT administration. Parameters of interest included maximum plasma concentration (C(max)), time to reach C(max) (t(max)), area under the plasma concentration-time curve from time zero to 8 hours (AUC(8)), and AUC from time zero to the median t(max) (AUC(tmax)(')). Adverse events were monitored throughout the study. Oral mucosal examinations and measurements of vital signs were performed at intervals up to 8 hours following FBT administration.Sixteen patients, 8 with and 8 without oral mucositis, received FBT and completed the study. The severity of oral mucositis was mild in the patients exhibiting this condition. Median C(max) values were comparable: 1.14 ng/mL (range 0.26-2.69 ng/mL) in patients with mucositis, and 1.21 ng/mL (range 0.21-2.34 ng/mL) in patients without mucositis. The t(max) was not significantly different in the two groups: median t(max) was 25.0 min (range 15-45 min) in patients with mucositis and 22.5 min (range 10-121 min) in patients without mucositis. Median AUC(tmax') values were 0.17 ng . h/mL (range 0.04-0.52 ng . h/mL) in patients with mucositis, and 0.20 ng . h/mL (range 0.00-0.65 ng . h/mL) in patients without mucositis. The corresponding AUC(8) values were 2.05 ng . h/mL (range 1.16-3.83 ng . h/mL) and 1.55 ng . h/mL (range 0.74-3.07 ng . h/mL), respectively. FBT was generally well tolerated in this small group. No application site adverse events or changes in oral mucosal assessments were reported.The absorption profile of a single dose of FBT 200 microg was similar in patients with or without mild oral mucositis. The compound was generally well tolerated.